PDCD1编码的免疫检查点受体PD-1是T细胞中的一个关键肿瘤抑制因子，经常在T细胞非霍奇金淋巴瘤（T-NHLs）中被失活。PDCD1缺失的最高频率出现在晚期疾病中，预示着较差的预后。然而，PD-1信号的肿瘤抑制机制仍未知。在这里，我们利用可操作的小鼠模型和原发患者样本，证明了PD-1信号通过限制糖酵解能量和乙酰辅酶A（CoA）的生成来抑制T细胞恶性肿瘤。此外，PD-1失活增强了ATP柠檬酸裂酶（ACLY）活性，生成胞外线粒体乙酰辅酶A用于组蛋白乙酰化，进而促使活化蛋白1（AP-1）转录因子的高活性。相反，药物抑制ACLY阻碍了PD-1缺乏的T-NHLs中异常的AP-1信号传导，并对这些肿瘤具有毒性作用。我们的数据揭示了PDCD1突变的T-NHL中基因型特异性的易感性，同时确定了PD-1作为AP-1活性的调节因子。© 2023. 作者。

The PDCD1-encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells that is recurrently inactivated in T cell non-Hodgkin lymphomas (T-NHLs). The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis. However, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Here, using tractable mouse models for T-NHL and primary patient samples, we demonstrate that PD-1 signaling suppresses T cell malignancy by restricting glycolytic energy and acetyl coenzyme A (CoA) production. In addition, PD-1 inactivation enforces ATP citrate lyase (ACLY) activity, which generates extramitochondrial acetyl-CoA for histone acetylation to enable hyperactivity of activating protein 1 (AP-1) transcription factors. Conversely, pharmacological ACLY inhibition impedes aberrant AP-1 signaling in PD-1-deficient T-NHLs and is toxic to these cancers. Our data uncover genotype-specific vulnerabilities in PDCD1-mutated T-NHL and identify PD-1 as regulator of AP-1 activity.© 2023. The Author(s).